Wesley Matthews played high school basketball at James Madison Memorial High School in Madison, Wisconsin. He was named the 2005 Wisconsin Mr. Basketball winner.

Matthews elected to attend Marquette University. Due to a lack of height on the Marquette roster, Matthews learned to play against bigger opponents. On January 7, 2009, Matthews set a school record for field goal accuracy (minimum 10 attempts) when he went 10-10, scoring 23 points.

Matthews played four seasons at Marquette. He went undrafted after the 2009 NBA Draft.

After going undrafted in 2009, Matthews joined the Utah Jazz for the Orlando Summer League and the Sacramento Kings for the Las Vegas Summer League. He signed a one-year deal with the Jazz. 

On July 10, 2010, Matthews signed a five-year, $34 million deal with the Portland Trail Blazers. He averaged 15.9 points per game in his first season in Portland. Matthews played in 250 consecutive games, earning him the nickname “Iron Man”.  Matthews became the Trail Blazers all-time leader in career three-point field goals made on January 17, 2015 (774). He tore his ACL in a game two months later and missed the rest of the season.

On July 9, 2015, Matthews signed a four-year deal with the Dallas Mavericks. He hit 10 three-pointers in a game on December 6th. On February 13, 2018, Matthews became the seventh player in Mavericks’ history to make 500 three-pointers with the team. In January of the following year, he became the sixth player in Mavs’ history to make 600 three-pointers. He was also the first undrafted player in NBA history to make 1,500 three-pointers.

On January 21, 2019, Matthews was involved in a multi-player deal that sent him to the New York Knicks. He was waived a week later. Three days after being waived, he was signed by the Indiana Pacers. On July 12, 2019, Matthews signed with the Milwaukee Bucks.